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copper-boosting compounds: a novel concept for antimycobacterial drug discovery.we and others recently identified copper resistance as important for virulence of mycobacterium tuberculosis. here, we introduce a high-throughput screening assay for agents that induce a copper hypersensitivity phenotype in m. tuberculosis and demonstrate that such copper-boosting compounds are effective against replicating and nonreplicating m. tuberculosis strains.201323254420
infection of macrophages with mycobacterium tuberculosis induces global modifications to phagosomal function.the phagosome is a central mediator of both the homeostatic and microbicidal functions of a macrophage. following phagocytosis, mycobacterium tuberculosis (mtb) is able to establish infection through arresting phagosome maturation and avoiding the consequences of delivery to the lysosome. the infection of a macrophage by mtb leads to marked changes in the behaviour of both the macrophage and the surrounding tissue as the bacterium modulates its environment to promote its survival. in this study, ...201323253353
role of tnf-alpha, ifn-gamma, and il-10 in the development of pulmonary tuberculosis.host immune response against mycobacterium tuberculosis is mediated by cellular immunity, in which cytokines and th1 cells play a critical role. in the process of control of the infection by mycobacteria, tnf-alpha seems to have a primordial function. this cytokine acts in synergy with ifn-gamma, stimulating the production of reactive nitrogen intermediates (rnis), thus mediating the tuberculostatic function of macrophages, and also stimulating the migration of immune cells to the infection site ...201223251798
association of diabetes and tuberculosis: impact on treatment and post-treatment outcomes.to determine the clinical consequences of pulmonary tuberculosis (tb) among patients with diabetes mellitus (dm).201323250998
elastin, a novel extracellular matrix protein adhering to mycobacterial antigen 85 complex.the antigen 85 complex (ag85) consists of three predominantly secreted proteins (ag85a, ag85b, and ag85c), which play a key role in the mycobacterial pathogenesis and also possess enzymatic mycolyltransferase activity involved in cell wall synthesis. ag85 is not only considered to be a virulence factor because its expression is essential for intracellular survival within macrophages, but also because it contributes to adherence, invasion, and dissemination of mycobacteria in host cells. in this ...201323250738
the molecular diagnosis of pelvic tuberculosis: a case report.tuberculosis is a re-emerging infectious disease. a retrospective analysis was made of the clinical history of a 48-year-old woman in april 2009; she was a secretary at a third-level hospital living in an urban area. pelvic tubercular infection was suggested as a possible diagnosis; spoligotyping molecular methodology was used on a peritoneal secretion sample to confirm such diagnosis and confirmed the presence of mycobacterium tuberculosis (octal code 777777777760771, sit 53, family t1).201223250377
the study of novel dna vaccines against tuberculosis: induction of pathogen-specific ctl in the mouse and monkey models of tuberculosis.hsp65 + il-12 dna vaccine showed higher protective efficacy compared with bcg in both mouse and monkey models of tb. it induced the tb-specific ctl in the mouse model of tb, while little level of activity was observed after the injection of bcg. it also showed strong therapeutic efficacy against mdr-tb. in the monkey model, the vaccine augmented the production of ifn-γ and il-2 from pbl and the therapeutic effect was correlated with the level of il-2. we next evaluated the potential of dna vacci ...201323249543
evaluation of the effect of humulus lupulus alcoholic extract on rifampin-sensitive and resistant isolates of mycobacterium tuberculosis.the increasing incidence of multi drug resistance tuberculosis (mdr-tb) and extensively drug resistance tb (xdr-tb) worldwide highlight the urgent need to search for newer anti-tuberculosis compounds. it has been determined that pharmaceutical plant, hops (humulus lupulus), possesses some antibacterial effect. in this study, the antimycobacterial effect of this plant on rifampin sensitive and resistant strains of mycobacterium tuberculosis were examined. sensitivity and resistance of 37 iranian ...201223248674
the heterogeneous evolution of multidrug-resistant mycobacterium tuberculosis.recent surveillance data of multidrug-resistant tuberculosis (mdr-tb) reported the highest rates of resistance ever documented. as further amplification of resistance in mdr strains of mycobacterium tuberculosis occurs, extensively drug-resistant (xdr) and totally drug-resistant (tdr) tb are beginning to emerge. although for the most part, the epidemiological factors involved in the spread of mdr-tb are understood, insights into the bacterial drivers of mdr-tb have been gained only recently, lar ...201323245857
effect of carbon monoxide on mycobacterium tuberculosis pathogenesis.the intracellular pathogen mycobacterium tuberculosis (mtb) is exposed to multiple host antimicrobial pathways, including toxic gases such as superoxide, nitric oxide and carbon monoxide (co). to survive, mycobacteria evolved mechanisms to resist the toxic environment, and in this review we focus on a relatively new field, namely, the role of macrophage heme oxygenase and its enzymatic product co in mtb pathogenesis. in particular, we focus on (i) the induction of heme oxygenase during mtb infec ...201223244630
a pilot external quality assurance programme for line-probe assay detection of anti-tuberculosis drug resistance.multidrug-resistant tuberculosis (mdr-tb; resistance to isoniazid and rifampicin) is difficult to detect and control. line-probe assays (lipa) are widely used for the rapid detection of mdr-tb.201323244351
effect of mycobacterial secretory proteins on the cellular integrity and cytokine profile of type ii alveolar epithelial cells.pulmonary tuberculosis (tb) is caused by mycobacterium tuberculosis (m. tb). in lungs, alveolar macrophages and type ii alveolar epithelial cells serve as a replicative niche for this pathogen. secretory proteins released by actively replicating tubercle bacilli are known to interact with host cells at the initial stages of infection. to understand the role of these cells in tb pathogenesis, it is important to identify the mycobacterial components involved in interaction with alveolar epithelial ...201223243342
minimal inhibitory concentrations of first-line drugs of multidrug-resistant tuberculosis isolates.the treatment of multidrug-resistant (mdr) and extensively drug-resistant (xdr) tuberculosis (tb) is consistently difficult. besides resistances, drug availability can be problematic and costs for therapy are high.201223243341
mycobacterium tuberculosis metabolism and host interaction: mysteries and paradoxes.metabolism is a widely recognized facet of all host-pathogen interactions. knowledge of its roles in pathogenesis, however, remains comparatively incomplete. existing studies have emphasized metabolism as a cell autonomous property of pathogens used to fuel replication in a quantitative, rather than qualitatively specific, manner. for mycobacterium tuberculosis, however, matters could not be more different. m. tuberculosis is a chronic facultative intracellular pathogen that resides in humans as ...201323242856
il-17 and ifn-γ production in peripheral blood following bcg vaccination and mycobacterium tuberculosis infection in human.during mycobacterium tuberculosis (mtb) infection, cells of the immune system rely on cytokines to regulate the activity of other immune and structural cells such as ifn-gamma and il-4. recent studies suggest that th17 cells secreting il-17 may play a potential role in tuberculosis (tb) development.201223242733
function of ssdna aptamer and aptamer pool against mycobacterium tuberculosis in a mouse model.novel antibacterial agents against mycobacterium tuberculosis (mtb) are crucial due to the high infection and mortality rates associated with the disease. our previous study confirmed that aptamers from a whole bacterium obtained by the systematic evolution of ligands by exponential enrichment method specifically bound to the mtb virulent strain (h37rv). in the present study, the function of aptamers against mtb in a mouse model was further determined. it was demonstrated that the nk2 aptamer ha ...201323242377
microparticles from mycobacteria-infected macrophages promote inflammation and cellular migration.mycobacterium tuberculosis infection is characterized by a strong inflammatory response whereby a few infected macrophages within the granuloma induce sustained cellular accumulation. the mechanisms coordinating this response are poorly characterized. we hypothesized that microparticles (mps), which are submicron, plasma membrane-derived vesicles released by cells under both physiological and pathological conditions, are involved in this process. aerosol infection of mice with m. tuberculosis in ...201323241892
is adjuvant therapy a potential road for fighting mycobacterium tuberculosis resistance? 201223241177
synthesis and evaluation of α-thymidine analogues as novel antimalarials.plasmodium falciparum thymidylate kinase (pftmpk) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of mycobacterium tuberculosis tmpk (mttmpk). starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of pftmpk and furthermore showed moderate inhibition of parasite growth. the stru ...201223240776
long-lived memory b-cell responses following bcg vaccination.the role of t-cells in immunity against mycobacterium tuberculosis (m. tuberculosis) infection has been extensively studied, however, that of b-cells still remains comparatively unexplored. in this study, we determined the presence and frequencies of mycobacteria-specific memory b-cells (mbcs) in peripheral blood from clinically healthy, bacillus calmette guerin (bcg) vaccinated (n = 79) and unvaccinated (n = 14) donors. purified protein derivative (ppd)-specific mbcs were present in most donors ...201223240017
cd4-cd8-αβ and γδ t cells display inflammatory and regulatory potentials during human tuberculosis.t-cells play an important role controlling immunity against pathogens and therefore influence the outcome of human diseases. although most t-lymphocytes co-express either cd4 or cd8, a smaller t-cell subset found the in the human peripheral blood that expresses the αβ or γδ t-cell-receptor (tcr) lacks the cd4 and cd8 co-receptors. these double negative (dn) t-cells have been shown to display important immunological functions in human diseases. to better understand the role of dn t-cells in human ...201223239994
molecular epidemiology of mycobacterium tuberculosis in the united states-affiliated pacific islands.the united states-affiliated pacific islands (usapi) are part of the us national tuberculosis (tb) surveillance system and use laboratory services contracted through a cooperative agreement with the centers for disease control and prevention (cdc). in 2004, the cdc established the national tuberculosis genotyping service, a system to genotype 1 isolate from each culture-confirmed case of tb. to describe the molecular epidemiology of tb in the region, we examined all mycobacterium tuberculosis is ...201423239749
getting across the cell envelope: mycobacterial protein secretion.protein secretion is an essential determinant of mycobacterial virulence. mycobacterium tuberculosis has a unique cell envelope consisting of two lipid bilayers, which requires dedicated protein secretion pathways. the conserved general sec and tat translocation systems are responsible for protein transport across the inner membrane and are both essential. additionally, the accessory sec pathway specifically contributes to virulence. how transport of sec/tat substrates across the outer membrane ...201323239236
targeting the deep lungs, poloxamer 407 and a cpg oligonucleotide optimize immune responses to mycobacterium tuberculosis antigen 85a following pulmonary delivery.the current bacille calmette-guérin vaccine provides variable protection against tuberculosis and new vaccination approaches are urgently needed. pulmonary vaccination could be the best way to induce a protective immunity against mycobacterium tuberculosis as it targets its natural site of infection. the aim of this study was to investigate the potential of poloxamer 407 (p407) combined with a cpg oligonucleotide (cpg) to enhance immune responses to m. tuberculosis antigen 85a (ag85a) following ...201323238272
[development and application of homologous recombination knockout system in mycobacterium tuberculosis].we developed a homologous recombination system to make marker-free mutants in mtb in an easy screening way.201223236850
ifn-γ from cd4 t cells is essential for host survival and enhances cd8 t cell function during mycobacterium tuberculosis infection.ifn-γ is necessary in both humans and mice for control of mycobacterium tuberculosis. cd4 t cells are a significant source of ifn-γ during acute infection in mice and are required for control of bacterial growth and host survival. however, several other types of cells can and do produce ifn-γ during the course of the infection. we sought to determine whether ifn-γ from sources other than cd4 t cells was sufficient to control m. tuberculosis infection and whether cd4 t cells had a role in additio ...201323233724
mycobacterium tuberculosis controls microrna-99b (mir-99b) expression in infected murine dendritic cells to modulate host immunity.mycobacterium tuberculosis resides and replicates within host phagocytes by modulating host microbicidal responses. in addition, it suppresses the production of host protective cytokines to prevent activation of and antigen presentation by m. tuberculosis-infected cells, causing dysregulation of host protective adaptive immune responses. many cytokines are regulated by micrornas (mirnas), a newly discovered class of small noncoding rnas, which have been implicated in modulating host immune respo ...201323233675
the mm2qm tool for combining docking, molecular dynamics, molecular mechanics, and quantum mechanics.the use of the mm2qm tool in a combined docking + molecular dynamics (md) + molecular mechanics (mm) + quantum mechanical (qm) binding affinity prediction study is presented, and the tool itself is discussed. the system of interest is mycobacterium tuberculosis (mtb) pantothenate synthetase in complexes with three highly similar sulfonamide inhibitors, for which crystal structures are available. starting from the structure of mtb pantothenate synthetase in the "open" conformation and following t ...201323233437
mycobacterium tuberculosis dna fingerprint clusters and its relationship with rd(rio) genotype in brazil.mycobacterium tuberculosis (mtb) strains designated as rd(rio) are responsible for a large cluster of new cases of tuberculosis (tb) in rio de janeiro. they were previously shown to be associated with severe manifestations of tb. here, we used three genotyping methods (is6110 rflp, spoligotyping, and multiplex pcr) to characterize rd(rio) and non-rd(rio) strains from the metropolitan area of vitória, state of espirito santo in southeast brazil to determine strain diversity and transmission patte ...201323232111
proficiency of drug susceptibility testing for mycobacterium tuberculosis in taiwan, 2007-2011.authorised clinical mycobacteriology laboratories in taiwan.201323232011
evaluation of high-mobility group box 1 protein concentration in serum of patients with m. tuberculosis infection.infection with mycobacterium tuberculosis is accompanied by an intense inflammatory response. recently, a new mediator of inflammation, hmgb1 protein has been identified that contributes to acute lung injury. however, its role in the systemic inflammatory response in tuberculosis has not been thoroughly investigated. we investigated the systemic levels of hmgb1 and tnf-α in patients with active and latent lung tuberculosis as a prognostic marker of disease activity. the study was performed to 70 ...201323231044
current and novel approaches to vaccine development against tuberculosis.antibiotics and vaccines are the two most successful medical countermeasures that humans have created against a number of pathogens. however a select few e.g., mycobacterium tuberculosis (mtb), the causative agent of tuberculosis (tb) have evaded eradication by vaccines and therapeutic approaches. tb is a global public health problem that kills 1.4 million people per year. the past decade has seen significant progress in developing new vaccine candidates, but the most fundamental questions in un ...201223230563
immunological mechanisms by which concomitant helminth infections predispose to the development of human tuberculosis.helminthic infections afflict over 1.5 billion people worldwide, while mycobacterium tuberculosis infects one third of the world's population, resulting in 2 million deaths per year. although tuberculosis and helminthic infections coexist in many parts of the world, and it has been demonstrated that the t-helper 2 and t-regulatory cell responses elicited by helminths can affect the ability of the host to control mycobacterial infection, it is still unclear whether helminth infections in fact aff ...201223230324
rapid preparation of mycobacterium n-glycolyl lipid i and lipid ii derivatives: a biocatalytic approach.breaking down barriers: a rapid, inexpensive preparation of the structurally complex mycobacterial n-glycolyl lipid i, lipid ii, and their analogues from a range of different synthetic n-glycolyl and n-glycinyl park's nucleotides is described (see scheme). the biotransformations were catalyzed by a readily available biocatalyst obtained from a bacterial cell-free membrane fraction. the unnatural n-glycinyl lipid ii was found to be a substrate of mycobacterium tuberculosis (mtb) transglycosylase, ...201323229320
antitubercular pharmacodynamics of phenothiazines.phenothiazines have been shown to exhibit in vitro and in vivo activity against mycobacterium tuberculosis (mtb) and multidrug-resistant mtb. they are predicted to target the genetically validated respiratory chain component type ii nadh:quinone oxidoreductase (ndh). using a set of compounds containing the phenothiazine pharmacophore, we have (i) investigated whether chemical validation data support the molecular target and (ii) evaluated pharmacophore tractability for further drug development.201323228936
a new multilocus sequence analysis scheme for mycobacterium tuberculosis.tuberculosis remains one of the most serious infectious diseases in the world. in this study, a scheme of mycobacterium tuberculosis (m. tuberculosis) multilocus sequence analysis (mlsa) was established for the phylogenetic and epidemiology analysis.201223228831
enhancement of immune response to a dna vaccine against mycobacterium tuberculosis ag85b by incorporation of an autophagy inducing system.dna vaccines are a promising new generation of vaccines that can elicit an immune response using dna encoding the antigen of interest. the efficacy of these vaccines, however, still needs to be improved. in this study, we investigated the effect of autophagy on increasing the efficacy of a candidate dna vaccine against mycobacterium tuberculosis (mtb), a causative agent of tuberculosis. low molecular weight chitosan was used to encapsulate plasmid dna containing a gene encoding mtb antigen 85b ( ...201323228812
diversity of mycobacterium tuberculosis isolates from new pulmonary tuberculosis cases in addis ababa, ethiopia.understanding the genetic diversity of mycobacterium tuberculosis is needed for a better understanding of the epidemiology of tb and could have implications for the development of new diagnostics, drugs, and vaccines. m. tuberculosis isolates were characterized using spoligotyping and were compared with the spoidb4 database of the pasteur institute of guadeloupe. a total of 53 different patterns were identified among 192 isolates examined. 169 of the isolates were classified into one of the 33 s ...201223227330
molecular typing of mycobacterium tuberculosis isolates circulating in henan, central china.the aim of this study was to characterize the genotypes of mycobacterium tuberculosis (mt) in isolates obtained from henan, china, and to study the distribution features of beijing strains in henan. a total of 443 mt strains isolated in henan province were tested for susceptibility to isonicotinylhydrazide (inh), rifampicin (rfp), ethambutol (emb) and streptomycin (sm), and genotyped by spoligotyping. the clustering of genotypes revealed 4 gene clusters (beijing and beijing-like, t, manu, and s ...201223226754
high isoniazid resistance rates in rifampicin susceptible mycobacterium tuberculosis pulmonary isolates from pakistan.rapid new diagnostic methods (including xpert mtb/rif assay) use rifampicin resistance as a surrogate marker for multidrug resistant tuberculosis. patients infected with rifampicin susceptible strains are prescribed first line anti-tuberculosis therapy. the roll out of such methods raises a concern that strains with resistance to other first line anti-tuberculosis drugs including isoniazid will be missed and inappropriate treatment given. to evaluate implications of using such methods review of ...201223226311
host cell-induced components of the sulfate assimilation pathway are major protective antigens of mycobacterium tuberculosis.new therapies to control tuberculosis are urgently required because of the inability of the only available vaccine, bcg, to adequately protect against tuberculosis. here we demonstrate that proteins of the mycobacterium tuberculosis sulfate-assimilation pathway (sap) represent major immunogenic targets of the bacillus, as defined by strong t-cell recognition by both mice and humans infected with m. tuberculosis. sap proteins displayed increased expression when m. tuberculosis was resident within ...201323225904
studies of inositol 1-phosphate analogues as inhibitors of the phosphatidylinositol phosphate synthase in mycobacteria.we previously reported a novel pathway for the biosynthesis of phosphatidylinositol in mycobacteria via phosphatidylinositol phosphate (pip) [morii h., ogawa, m., fukuda, k., taniguchi, h., and koga, y (2010) j. biochem. 148, 593-602]. pip synthase in the pathway is a promising target for the development of new anti-mycobacterium drugs. in the present study, we evaluated the characteristics of the pip synthase of mycobacterium tuberculosis. four types of compounds were chemically synthesized bas ...201323225597
endovascular repair of mycotic aneurysm of the descending thoracic aorta: diagnostic and therapeutic dilemmas-two case reports with 1-year follow-up.a mycotic aneurysm of the thoracic aorta is a rare diagnosis with high mortality. we present two cases of endovascular reconstruction of mycotic descending thoracic aorta. specific or nonspecific bacterial or other infectious agent in serial samples of blood, urine, cerebrospinal fluid, and pleural puncture was not detected in the first case, but we found in sputum sample mycobacterium tuberculosis in the second patient. we empirically began by administering broad-spectrum intravenous antibiotic ...201323225505
serum iron profile and elisa-based detection of antibodies against the iron-regulated protein hupb of mycobacterium tuberculosis in tb patients and household contacts in hyderabad (andhra pradesh), india.hupb is a 28 kda cell-wall-associated protein co-expressed with the siderophores mycobactin and carboxymycobactin in iron-limited mycobacterium tuberculosis. hupb is expressed in vivo and anti-hupb antibodies are present in the serum of tb patients.201323222944
high-resolution transcriptome and genome-wide dynamics of rna polymerase and nusa in mycobacterium tuberculosis.to construct a regulatory map of the genome of the human pathogen, mycobacterium tuberculosis, we applied two complementary high-resolution approaches: strand-specific rna-seq, to survey the global transcriptome, and chip-seq, to monitor the genome-wide dynamics of rna polymerase (rnap) and the anti-terminator nusa. although nusa does not bind directly to dna, but rather to rnap and/or to the nascent transcript, we demonstrate that nusa interacts with rnap ubiquitously throughout the chromosome, ...201323222129
interferon-γ elispot as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial.biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (ltbi) and predict reactivation tb disease are urgently required.201323220919
capreomycin supergenerics for pulmonary tuberculosis treatment: preparation, in vitro, and in vivo characterization.the pulmonary route is one of the main strategies investigated to improve tuberculosis therapy. the aim of this study was to develop a simple and scalable method to produce capreomycin inhalable powders to use as supergeneric. in vitro antimycobacterial activity and in vivo acute toxicity were assessed using agar proportion susceptibility test on mycobacterium tuberculosis and chicken chorioallantoic membrane assay, respectively. capreomycin and three different hydrophobic counterions, namely ol ...201323220041
the evolutionary landscape of the mycobacterium tuberculosis genome.mycobacterium tuberculosis is one of the most deadly human pathogens. the major mechanism for the adaptations of m. tuberculosis is nucleotide substitution. previous studies have relied on the nonsynonymous-to-synonymous substitution rate (dn/ds) ratio as a measurement of selective constraint based on the assumed selective neutrality of synonymous substitutions. however, this assumption has been shown to be untrue in many cases. in this study, we used the substitution rate in intergenic regions ...201323219994
the il-17f sequence variant is associated with susceptibility to tuberculosis.the interleukin (il)-17 gene plays a key role in host defence against infections from microbes, including mycobacterium tuberculosis. genetic factors contribute to host defence. however, whether genetic variation in il-17 is associated with altered susceptibility to tuberculosis is unknown. a total of 596 pulmonary tuberculosis (ptb) patients, 176 extra-pulmonary tuberculosis (eptb) patients, and 622 control patients from a chinese han population were recruited. two single-nucleotide polymorphis ...201323219503
the candidate tuberculosis vaccine mtb72f/as02 in ppd positive adults: a randomized controlled phase i/ii study.prevention of tuberculosis (tb) through vaccination would substantially reduce the global tb burden. mtb72f/as02 is a candidate tb vaccine shown to be immunogenic and well tolerated in ppd-negative adults. we evaluated the safety and immunogenicity of mtb72f/as02 in mycobacterium-primed adults (bcg-vaccinated, or infected adults who had received post-exposure chemoprophylaxis or treatment for pulmonary tb disease). in this observer-blind controlled trial, 20 bcg-vaccinated adults and 18 adults p ...201323219236
miru-vntr profiles of three major mycobacterium tuberculosis spoligotypes found in western india.we performed 12 loci miru-vntr on 327 mycobacterium tuberculosis (mtb) isolates belonging to three major spoligotypes manu1, cas1_delhi and beijing from mumbai, western india and two proximal rural locations. complete allele and drug susceptibility data was available for 232 isolates. these included 143 manu1 (st100), 65 cas1_delhi (st26) and 24 beijing (st1) isolates. of the 232 isolates, 26 were rural consisting 6 cas1_delhi and 20 manu1 isolates. using eburst multi-locus sequence typing (mlst ...201323219234
highly precise measurement of kinetic isotope effects using 1h-detected 2d [13c,1h]-hsqc nmr spectroscopy.a new method is presented for measuring kinetic isotope effects (kies) by (1)h-detected 2d [(13)c,(1)h]-heteronuclear single quantum coherence (hsqc) nmr spectroscopy. the high accuracy of this approach was exemplified for the reaction catalyzed by glucose-6-phosphate dehydrogenase by comparing the 1-(13)c kie with the published value obtained using isotope ratio mass spectrometry. high precision was demonstrated for the reaction catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase from ...201223215000
screening, isolation, taxonomy and fermentation of an antibiotic producer streptomyces xinghaiensis from soil capable of acting against linezolid resistant strains.linezolid resistant cultures are emerging in hospitals. in the present study 3 soil actinomycetes were isolated in a screening programme having potential to produce antibiotic against linezolid resistant cases. one culture was coded as rk-46 and further studied. the micromorphology, biochemical tests and 16s ribosomal dna gene sequence analysis were conducted to know the identity of the culture and was found as a strain of streptomyces xinghaiensis. the culture produced antibiotic active against ...201223214266
[evaluation of genotype mtbdrsl for testing resistance of mycobacterium tuberculosis isolates to fluoroquinlone, aminoglycoside, and ethambutol].to evaluate the ability of genotype mtbdrsl (hain lifescience, germany) in detecting resistance to fluoroquinolone (fq), aminoglycoside (ag), and ethambutol (eb).201223214120
roles of mucosal immunity against mycobacterium tuberculosis infection.mycobacterium tuberculosis (mtb), the causative agent of tuberculosis (tb), is one of the world's leading infectious causes of morbidity and mortality. as a mucosal-transmitted pathogen, mtb infects humans and animals mainly through the mucosal tissue of the respiratory tract. apart from providing a physical barrier against the invasion of pathogen, the major function of the respiratory mucosa may be to serve as the inductive sites to initiate mucosal immune responses and sequentially provide th ...201223213508
tuberculosis is not a risk factor for primary biliary cirrhosis: a review of the literature.primary biliary cirrhosis (pbc) is a progressive cholestatic liver disease characterised serologically by cholestasis and the presence of high-titre antimitochondrial antibodies, and histologically by chronic nonsuppurative cholangitis and granulomata. as pbc is a granulomatous disease and mycobacterium tuberculosis is the most frequent cause of granulomata, a causal relation between tuberculosis and pbc has been suggested. attempts to find serological evidence of pbc-specific autoantibodies suc ...201223213506
evaluation of the filter paper ip-10 tests in school children after exposure to tuberculosis: a prospective cohort study with a 4-year follow-up.the prevalence of active tuberculosis (tb) is low in finland, but outbreaks do occur. following exposure national guidelines recommend either tuberculosis skin test or interferon-γ-release assay-testing of asymptomatic children. the aim of this study was to compare quantiferon-tb gold in-tube test (qft) and interferon-γ-inducible protein (ip-10) release assay for detection of mycobacterium tuberculosis infection following exposure to tb in a primary school.201223212994
structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.a series of salicylanilides was synthesized based on a high-throughput screening hit against mycobacterium tuberculosis. a free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. we synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. u ...201323211970
ligand diffusion on protein surface observed in molecular dynamics simulation.the process of binding of small ligands to dihydrofolate reductase protein has been investigated using all-atom molecular dynamics simulations. the existence of a mechanism that facilitates the search of the binding site by the ligand is demonstrated. the mechanism consists of ligand diffusing on the protein's surface. it has been discussed in the literature before, but has not been explicitly confirmed for realistic molecular systems. the strength of this nonspecific binding is roughly estimate ...201226290975
"proof-of-concept" evaluation of an automated sputum smear microscopy system for tuberculosis diagnosis."tbdx" is an innovative smear microscopy system that automatically loads slides onto a microscope, focuses and digitally captures images and then classifies smears as positive or negative using computerised algorithms.201223209666
modelling hiv and mtb co-infection including combined treatment strategies.a new host-pathogen model is described that simulates hiv-mtb co-infection and treatment, with the objective of testing treatment strategies. the model includes cd4+ and cd8+ t cells, resting and activated macrophages, hiv and mycobacterium tuberculosis (mtb). for tb presentation at various stages of hiv disease in a co-infected individual, combined treatment strategies were tested with different relative timings of treatment for each infection. the stages were early hiv disease, late hiv diseas ...201223209581
relatively low level of antigen-specific monocytes detected in blood from untreated tuberculosis patients using cd4+ t-cell receptor tetramers.the in vivo kinetics of antigen-presenting cells (apcs) in patients with advanced and convalescent tuberculosis (tb) is not well characterized. in order to target mycobacterium tuberculosis (mtb) peptides- and hla-dr-holding monocytes and macrophages, 2 mtb peptide-specific cd4(+) t-cell receptor (tcr) tetramers eu and hu were successfully constructed. peripheral blood (pbl) samples from inpatients with advanced pulmonary tb (ptb) were analyzed using flow cytometry, and the percentages of tetram ...201223209409
putative compensatory mutations in the rpoc gene of rifampin-resistant mycobacterium tuberculosis are associated with ongoing transmission.rifampin resistance in clinical isolates of mycobacterium tuberculosis arises primarily through the selection of bacterial variants harboring mutations in the 81-bp rifampin resistance-determining region of the rpob gene. while these mutations were shown to infer a fitness cost in the absence of antibiotic pressure, compensatory mutations in rpoa and rpoc were identified which restore the fitness of rifampin-resistant bacteria carrying mutations in rpob. to investigate the epidemiological releva ...201323208709
rapid identification of extensively and extremely drug resistant tuberculosis from multidrug resistant strains; using pcr-rflp and pcr-sscp.resistance in mycobacterium tuberculosis is caused by mutations in genes encoding drug targets. investigators have already demonstrated the existence of mutations in codons 88 to 94 in the gyra gene and also in codons 1400, 1401, and 1483 of rrs gene among extensively and extremely drug resistant tuberculosis (xdr & xxdr-tb) strains. the aim of this study was to identify the xdr and xxdr-tb stains based on their mutational analysis.201223205246
population structure and circulating genotypes of drug-sensitive and drug-resistant mycobacterium tuberculosis clinical isolates in são paulo state, brazil.são paulo is the most populous brazilian state and reports the largest number of tuberculosis cases in the country annually (over 18,500). this study included 193 isolates obtained during the 2nd nationwide survey on mycobacterium tuberculosis drug resistance that was conducted in são paulo state and 547 isolates from a laboratory based study of drug resistance that were analyzed by the mycobacteria reference laboratory at the institute adolfo lutz. both studies were conducted from 2006 to 2008 ...201323201043
synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as mycobacterium tuberculosis thymidylate kinase inhibitors.we report the synthesis of 5'-modified thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of mycobacterium tuberculosis (tmpkmt). these analogues were evaluated for their capacity to inhibit tmpkmt and solely two 5'-modified thymidines were found to possess moderate inhibitory activity. in addition, a feasibility study of protecting groups for the 5-ch(2)oh moiety of 2'-deoxyuridines is described that enables to ...201323199481
molecular diagnostic methods for the detection of mycobacterium tuberculosis resistance: the potential of high-resolution melting analysis. 201223199393
quantitative proteomics for identifying biomarkers for tuberculous meningitis. 201223198679
[possible presence of a booster effect in people repeatedly exposed to mycobacterium tuberculosis demonstrated in a mycobacterium tuberculosis-specific interferon-gamma release assay].recently, several reports have described a waning response of mycobacterium tuberculosis (tb)-specific interferon-gamma (ifn-gamma) release assays (igras) performed years after the initial tb infection. since a considerable part of elderly people in japan was infected with tb in their youth, it was hypothesized that if the general population was screened with igras, the mean ifn-gamma value of positive subjects (positives) would be reduced as the age of the subjects increased. conversely, in sub ...201223198601
[the diagnosis of pulmonary tuberculosis].mycobacterium tuberculosis (m. tuberculosis) infects all organs in the body; however, lung infection is the primary lesion. the total number of infections is decreasing, but the percentage of infections in older people is rising. because this disease is due to infection with m. tuberculosis, the diagnosis requires the presence of m. tuberculosis. chest x-ray and ct are very powerful tools to suggest the presence of m. tuberculosis infection. pathological examination of the tissues also shows the ...201223198540
lipoproteins are major targets of the polyclonal human t cell response to mycobacterium tuberculosis.most vaccines and basic studies of t cell epitopes in mycobacterium tuberculosis emphasize water-soluble proteins that are secreted into the extracellular space and presented in the context of mhc class ii. much less is known about the role of ags retained within the cell wall. we used polyclonal t cells from infected humans to probe for responses to immunodominant ags in the m. tuberculosis cell wall. we found that the magnitude of response to secreted or cell wall intrinsic compounds was simil ...201323197260
prime-boost bcg vaccination with dna vaccines based in β-defensin-2 and mycobacterial antigens esat6 or ag85b improve protection in a tuberculosis experimental model.the world health organization (who) has estimated that there are about 8 million new cases annually of active tuberculosis (tb). despite its irregular effectiveness (0-89%), the bacillus calmette-guérin) bcg is the only vaccine available worldwide for prevention of tb; thus, the design is important of novel and more efficient vaccination strategies. considering that β-defensin-2 is an antimicrobial peptide that induces dendritic cell maturation through the tlr-4 receptor and that both esat-6 and ...201323196205
novel methodology to assess sputum smear microscopy quality in private laboratories.in south asia, it is estimated that 80% of patients choose to attend a private facility for their healthcare needs. although patients generally believe that the private-sector provides high quality services, private diagnostic laboratories are largely unregulated and little is known about the accuracy of results provided. this study assesses the accuracy of sputum smear microscopy for pulmonary tuberculosis diagnosis in private laboratories operating in karachi, pakistan. a novel evaluation meth ...201223193964
mycobacterium tuberculosis genotype beijing: about 15 strains and their part in mdr-tb outbreaks in algeria.within the framework of epidemiological surveillance by molecular typing tools conducted in the nrl on multi-resistant strains, the application of spoligotyping on a group of 390 strains consisting of 389 dr-mtb strains and 1 susceptible strain isolated from patients made it possible to detect the presence of 15 strains belonging to the beijing genotype. all 15 strains were genotyped by mtbdrplus. among the 15 strains, 11 were typed by rflp and 9 by miru-vntr. after analysis of the profiles obta ...201226785623
comparisons among the diagnostic methods used for the detection of extra-pulmonary tuberculosis in bangladesh.the present study was an attempt to establish a suitable method for the effective diagnosis of extra-pulmonary tuberculosis in bangladesh. in this regard, detection of mycobacterium tuberculosis from 390 different extra-pulmonary specimens was performed by bright-field microscopy, light-emitting diode fluorescence microscopy and lowenstein-jensen culture methods, followed by an extensive comparison among these methods. m. tuberculosis was detected in 53 cases through the conventional lowenstein- ...201226785622
quality indicators in a mycobacteriology laboratory supporting clinical trials for pulmonary tuberculosis.documentation of structured quality indicators for mycobacteriology laboratories supporting exclusively controlled clinical trials in pulmonary tuberculosis (ptb) is lacking.201226785621
the diagnostic efficiency of quantiferontb®-gold test in the diagnosis of tuberculous pleurisy.diagnosis of tuberculous pleurisy is difficult and better diagnostic tools are needed. interferon gamma release assays (igras) are in vitro immunologic diagnostic tests used to identify mycobacterium tb infections. they cannot differentiate between latent and active infections. as igra tests have recently been approved for the differential diagnosis of active tb, the diagnostic accuracy of the latest generation of igra were assessed to detect tuberculous pleurisy in this study.201226785620
tentative susceptibility testing breakpoint for the neuroleptic drug thioridazine, a treatment option for multi- and extensively drug resistant tuberculosis.new drugs against multi-(mdr) and extensively drug (xdr) resistant tuberculosis are urgently needed. while new candidate drugs are being developed, reinvestigation of already approved drugs available for other indications could be of value. the objective of this study is to determine tentative drug susceptibility testing strategies and breakpoints for thioridazine, a well-known and well-tolerated neuroleptic drug, which has been shown to be effective against drug resistant tuberculosis both in v ...201226785619
diagnostic performance of isothermal strand displacement amplification of mycobacterium tuberculosis is 6110 in tissue samples.visualized histopathological findings in tissue samples are not specific for tuberculosis while mycobacterial cultures from such specimens have low yields and long turn around times. a rapid, sensitive method is therefore needed for detection of mycobacterium tuberculosis in paucibacillary tissue samples.201226785618
impaired dendritic cell differentiation of cd16-positive monocytes in tuberculosis: role of p38 mapk.tuberculosis (tb) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent mycobacterium tuberculosis (mtb). blood monocytes (mos) represent an important source of dcs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. we evaluated whether the cd16(+)/cd16(-) mo ratio could be associated with the impaired mo differentiation into dcs fo ...201323192690
detecting tuberculosis infection in hiv-infected children: a study of diagnostic accuracy, confounding and interaction.accurate identification of mycobacterium tuberculosis infection in young and hiv-infected children could guide delivery of preventive therapy, improve resource utilization and help prevent tuberculosis.201323190784
design, synthesis, and x-ray analysis of a glycoconjugate bound to mycobacterium tuberculosis antigen 85c.tuberculosis (tb) is a global health threat with nearly 500 000 new cases of multidrug-resistant tb estimated to occur every year, so new drugs are desperately needed. a number of current antimycobacterial drugs work by interfering with the biosynthesis of key components of the mycolylarabinogalactan (mag). in light of this observation, other enzymes involved in the synthesis of the mag should also serve as targets for antimycobacterial drug development. one potential target is the antigen 85 (a ...201223190459
[adaptive changes of mycobacterium tuberculosis gene expression during the infectious process].mycobacterium tuberculosis causes an infection in humans with clinical manifestations varying from asymptomatic carriage of bacteria to rapidly progressing tuberculosis. infection outcomes depend on complex and still not fully understood interactions between the pathogenic bacteria and their host organism. gene expression changes in response to host defense mechanisms are needed for m. tuberculosis survival and functioning. this review focuses on the analysis of dynamic changes in the m. tubercu ...201223189553
diagnostic value of ex vivo pleural fluid interferon-gamma versus adapted whole-blood quantiferon-tb gold in tube assays in tuberculous pleural effusion.noninvasive diagnosis of pleural tuberculosis (tb) remains a challenge due to the paucibacillary nature of the disease. as mycobacterium tuberculosis (mtb)-specific t cells are recruited into pleural space in tb effusion; their indirect detection may provide useful clinical information.201223189099
successful treatment of bronchiolitis obliterans with organizing pneumonia in dialysis patient.a 42-year-old end stage renal disease (esrd) patient was admitted with fever, anorexia, malaise, non-productive cough, and dyspnea, of one-week duration. multiple cultures of the blood, sputum, and urine were negative for microorganisms. the possibility of bronchiolitis obliterans with organizing pneumonia (boop) was considered when patient with pulmonary infiltrate did not respond to conventional antibiotic therapy and frequent hemodyalisis. high-resolution computed tomography of the chest reve ...201223188959
[epidural abscess due to a mycobacterium tuberculosis strain with primary resistance to isoniazid and ethambutol].tuberculosis is primarily characterized by pulmonary involvement, however, one third of the cases exhibit extrapulmonary tuberculosis. in this report, a case of epidural abscess due to mycobacterium tuberculosis with primary resistance to isoniazid and ethambutol was presented. a 57-year-old male patient was admitted to emergency service with ten days history of weakness in legs, disability of walking and fever. neurological examination revealed paraplegia of lower extremities, numbness distal t ...201223188583
the manual mycobacteria growth indicator tube and the nitrate reductase assay for the rapid detection of rifampicin resistance of m. tuberculosis in low resource settings.tuberculosis (tb) is a disease of poverty that contributes significantly to ill-health in developing countries. drug resistant tb is a major challenge to disease control. early diagnosis and rapid determination of drug sensitivity is of paramount importance in eradication of tb. although automated liquid culture based methods are available for rapid detection of drug resistance, the high cost of these tests prevent them from being used routinely in low resource settings. this study compares two ...201223186045
lipocalin 2 regulates inflammation during pulmonary mycobacterial infections.pulmonary tuberculosis (tb), caused by the intracellular bacteria mycobacterium tuberculosis, is a worldwide disease that continues to kill more than 1.5 million people every year worldwide. the accumulation of lymphocytes mediates the formation of the tubercle granuloma in the lung and is crucial for host protection against m.tuberculosis infection. however, paradoxically the tubercle granuloma is also the basis for the immunopathology associated with the disease and very little is known about ...201223185529
genetic diversity and transmission characteristics of beijing family strains of mycobacterium tuberculosis in peru.beijing family strains of mycobacterium tuberculosis have attracted worldwide attention because of their wide geographical distribution and global emergence. peru, which has a historical relationship with east asia, is considered to be a hotspot for beijing family strains in south america. we aimed to unveil the genetic diversity and transmission characteristics of the beijing strains in peru. a total of 200 beijing family strains were identified from 2140 m. tuberculosis isolates obtained in li ...201223185395
a pilot study to determine genetic polymorphism in mycobacterium tuberculosis isolates in central india.this study was carried out to identify predominant spoligotypes responsible for transmission and prevalence of tuberculosis in central india since there is no data available about the genetic biodiversity of mycobacterium tuberculosis isolates from patients with tuberculosis in this region. 35 strains of mycobacterium tuberculosis were subjected to spoligotyping according to the standard protocol. a total of 25 strains out of the 35 (71.42%) could be grouped in to 6 clusters. the largest cluster ...201323183476
phenotypic and genotypic characteristics of drug resistance in mycobacterium tuberculosis isolates from pediatric population of chennai, india.multidrug-resistant tb (mdr-tb) has been reported in almost all parts of the world. childhood tb is accorded low priority by national tb control programs. probable reasons include diagnostic difficulties, limited resources, misplaced faith in bcg and lack of data on treatment. good data on the burden of all forms of tb among children in india are not available.201223183465
inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice.inhalable clofazimine-containing dry powder microparticles (cfm-dpi) and native clofazimine (cfm) were evaluated for activity against mycobacterium tuberculosis in human monocyte-derived macrophage cultures and in mice infected with a low-dose aerosol. both formulations resulted in 99% killing at 2.5 μg/ml in vitro. in mice, 480 μg and 720 μg cfm-dpi inhaled twice per week over 4 weeks reduced numbers of cfu in the lung by as much as log(10) 2.6; 500 μg oral cfm achieved a log(10) 0.7 reduction.201323183441
molecular typing and drug susceptibility of mycobacterium tuberculosis isolates from chongqing municipality, china.china's tuberculosis (tb) burden is second only to that of india worldwide. in chongqing, the largest municipality in southwestern china, although the prevalence of both tb and drug-resistant tb is higher than in other municipalities, the molecular characteristics and drug susceptibility phenotypes are poorly known. in this study, 297 mycobacterium tuberculosis isolates from chongqing were genotyped with spacer oligonucleotide typing (spoligotyping) and 28-locus miru-vntr (24-locus miru-vntr sch ...201323183314
rifampicin-induced transcriptome response in rifampicin-resistant mycobacterium tuberculosis.tuberculosis (tb) is still a major life-threatening infectious disease, within which especially the rise of multidrug resistant tb (mdr-tb) is currently worrying. this study focuses on mechanisms of development of rifampicin resistance, since rifampicin seems to play an important role in the development of mdr-tb. to provide further insight in rifampicin resistance, we performed a genome-wide transcriptional profile analysis for mycobacterium tuberculosis (m. tuberculosis) using microarray techn ...201323182912
the tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with mycobacterium tuberculosis.t cell ig and mucin domain 3 (tim3) is an inhibitory molecule involved in immune tolerance, autoimmune responses, and antiviral immune evasion. however, we recently demonstrated that tim3 and galectin-9 (gal9) interaction induces a program of macrophage activation that results in killing of mycobacterium tuberculosis in the mouse model of infection. in this study, we sought to determine whether the tim3-gal9 pathway plays a similar role in human pulmonary tb. we identified that pulmonary tb pati ...201223180819
rapid molecular tb diagnosis: evidence, policy making and global implementation of xpert mtb/rif.if tuberculosis (tb) is to be eliminated as a global health problem in the foreseeable future, improved detection of patients, earlier diagnosis and timely identification of rifampicin resistance will be critical. new diagnostics released in recent years have improved this perspective but they require investments in laboratory infrastructure, biosafety and staff specialisation beyond the means of many resource-constrained settings where most patients live. xpert mtb/rif, a new assay employing au ...201323180585
rv3080c regulates the rate of inhibition of mycobacteria by isoniazid through fabd.the mycobacterial fasii multi-enzyme complex has been identified to be a target of ser/thr protein kinases (stpks) of mycobacterium tuberculosis (mtb), with substrates, including the malonyl-coa:acp transacylase (fabd) and the β-ketoacyl-acp synthases kasa and kasb. these proteins are phosphorylated by various kinases in vitro. the present study links the correlation of fasii pathway with serine threonine protein kinase of mtb. in the preliminary finding, we have shown that mycobacterial protein ...201323180244
molecular biology of drug resistance in mycobacterium tuberculosis.tuberculosis (tb) has become a curable disease, thanks to the discovery of antibiotics. however, it has remained one of the most difficult infections to treat. most current tb regimens consist of 6-9 months of daily doses of four drugs that are highly toxic to patients. the purpose of these lengthy treatments is to completely eradicate mycobacterium tuberculosis, notorious for its ability to resist most antibacterial agents, thereby preventing the formation of drug resistant mutants. on the cont ...201323179675
mycobacterium tuberculosis s-adenosyl-l-homocysteine hydrolase is negatively regulated by ser/thr phosphorylation.s-adenosylhomocysteine hydrolase (sahh) is known as an ubiquitous player in methylation-based process that maintains the intracellular s-adenosylhomocysteine (sah) and s-adenosylmethionine (sam) equilibrium. given its crucial role in central metabolism in both eukaryotes and prokaryotes, it is assumed that sahh must be regulated, albeit little is known regarding molecular mechanisms governing its activity. we report here that sahh from mycobacterium tuberculosis can be phosphorylated by mycobact ...201323178568
utility of in vitro interferon-γ release assay in differential diagnosis between intestinal tuberculosis and crohn's disease.to evaluate the diagnostic utility of interferon-γ release assay (t-spot.tb) for the differential diagnosis between crohn's disease (cd) and intestinal tuberculosis (itb).201323176201
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